Reduction of serum matrix metalloproteinase 1 and matrix metalloproteinase 3 in rheumatoid arthritis patients following anti- tumour necrosis factor-alpha (cA2) therapy

Abstract

Matrix metalloproteinase (MMP)-1 and MMP-3 levels were measured in serum samples from rheumatoid arthritis (RA) patients undergoing a double-blinded placebo-controlled trial with the chimaeric anti-tumour necrosis factor (TNF)-alpha antibody cA2. Both MMP-1 (P < 0.015), but to a larger extent MMP-3 (P < 0.001) levels were elevated in all RA patients prior to the commencement of the trial compared with normal control sera. Following cA2 therapy, MMP-1 and MMP-3 levels were assessed in the placebo, and 1 and 10 mg/kg cA2-treated groups at 7, 14, 21 and 28 days. In both the 1 and the 10 mg/kg cA2-treated groups, a significant decrease in serum MMP-3 levels at all time points was observed, reducing maximally to 41% of pre-infusion values at day 7. MMP-1 levels were also reduced, but less dramatically than MMP-3, to 85% of pre-infusion values after 14 days in the 10 mg/kg cA2 treated group. In a separate non-placebo-controlled study, we also evaluated the tissue inhibitor of metalloproteinase (TIMP)-1 levels in plasma following cA2 infusion. Pre-infusion TIMP-1 levels were above the normal control range, but were significantly reduced (P < 0.035) 14 days after infusion to 72% of pre-infusion values. This study confirms previous reports that MMP-3 levels are elevated and correlate with measures of inflammation in RA, and furthermore demonstrate that serum MMP-3 and MMP-1 levels are downmodulated following anti-TNF-alpha antibody therapy. Whilst serum MMP-3 levels correlated with C-reactive protein (CRP) both prior to and following anti-TNF-alpha antibody therapy, it remains to be demonstrated that serum MMP-3 and/or MMP-1 levels reflect the cartilage and bone resorptive processes which are evident in this disease.

Biomarkers predict radiographic progression in early rheumatoid arthritis and perform well compared with traditional markers

“…In the present study, this was observed with levels of serum MMP-3, and although it is disappointing that we did not demonstrate changes in levels of other biochemical markers with MTX therapy, the study was not designed to address this question and the number of patients receiving MTX was limited. Our findings regarding serum MMP-3 levels in patients treated with MTX are consistent with the results of other studies that have shown a decrease in circulating MMP-3 levels with conventional DMARD therapy (43,44) or biologic therapy (45)(46)(47).…”

Disruption of tumor necrosis factor receptor p55 impairs collagen turnover in experimentally induced sclerodermic skin fibroblasts

“…It has also been reported that serum MMP-1 and MMP-3 were reduced in RA patients following anti-TNF therapy (43). Based on the present results, it should be kept in mind that these patients may be at risk for the side effect of scleroderma-like symptoms.…”

TNFα blockade in human diseases: Mechanisms and future directions

“…Synovial synthesis of TNFα, IL-1α and IL-1β were also reduced in RA patients following a single infusion of INF [29]. Reduced IL-1 levels result in reduced synthesis of MMP and other degradative enzymes, such as proMMP-1 and proMMP-3 [28,30,31].…”